The long term goal of therapy for HIV-1 infection should be to develop treatment regimens either to provide durable control of viral replication and/or eradicate the infection. Among the limitations of current therapy are the incomplete suppression of viral replication in many patients and the inability to affect the latent population of HIV-1 in quiescent CD4+ T-lymphocytes. While new agents in development may enhance the potency and durability of antretroviral treatments, these will not address the longer term problem of latency. The current program application proposes to evalaute the hypothesis that histone deacetylase (HDAC) inhibitors or other LTR-activating compounds can affect latent infection in a rhesus macaque model of retroviral latency. This hypothess is based on in vitro observations suggesting that HIV-1 latency is maintained by cellular mechanisms that control chromatin structure and that derepression of HIV-1 transcription can be induced by HDAC inhibitors without activating T-cells. In Project 1 of the application, we will identify and provide inhibitors as well as carry out a genome-scale siRNA screen to identify LTR-suppressing factors to identify different pathways for derepressing HIV-1 transcription. Additionally, we will develop critical assays required to establish an SIV model to test this hyothesis and support the evaluation of the HDAC inhibitor, vorinostat, and other LTR activators in vivo. The objectives of Project 1 include providing potent integrase inhibitors for a novel combination regimen (ART) that will be effective in SIV infection, providing vorinostat and other LTR-activating compounds and evaluating their effects on SIV latency, establishing pharmacodynamic assays for HDAC activity that will be used to select doses and identifying novel LTR-activators with enhanced potency and selectivity for testing in this model. The objective is to assess the susceptibility of the latent reserviprs to therapeutic intervention with the ultimate goal of identifying inhibitors and establishing treatment paradigms suitable for clinical testing.